In vivo epigenetic effects induced by engineered nanomaterials: A case study of copper oxide and laser printer-emitted engineered nanoparticles

Evidence continues to grow on potential environmental health hazards associated with engineered nanomaterials (ENMs). While the geno- and cytotoxic effects of ENMs have been investigated, their potential to target the epigenome remains largely unknown. The aim of this study is two-fold: 1) determining whether or not industry relevant ENMs can affect the epigenome in vivo and 2) validating a recently developed in vitro epigenetic screening platform for inhaled ENMs. Laser printer-emitted engineered nanoparticles (PEPs) released from nano-enabled toners during consumer use and copper oxide (CuO) were chosen since these particles induced significant epigenetic changes in a recent in vitro companion study. In this study, the epigenetic alterations in lung tissue, alveolar macrophages and peripheral blood from intratracheally instilled mice were evaluated. The methylation of global DNA and transposable elements (TEs), the expression of the DNA methylation machinery and TEs, in addition to general toxicological effects in the lung were assessed. CuO exhibited higher cell-damaging potential to the lung, while PEPs showed a greater ability to target the epigenome. Alterations in the methylation status of global DNA and TEs, and expression of TEs and DNA machinery in mouse lung were observed after exposure to CuO and PEPs. Additionally, epigenetic changes were detected in the peripheral blood after PEPs exposure. Altogether, CuO and PEPs can induce epigenetic alterations in a mouse experimental model, which in turn confirms that the recently developed in vitro epigenetic platform using macrophage and epithelial cell lines can be successfully utilized in the epigenetic screening of ENMs.     

Baicalin-loaded PEGylated lipid nanoparticles: characterization,pharmacokinetics, and protective effects on acute myocardial ischemia in rats

Context: Baicalin has many pharmacological activities, including protective function against myocardial ischemia by antioxidant effects and free radical scavenging activity. However, its rapid elimination half-life in plasma and poor water solubility limits its clinical efficacy.

Objective: Novel baicalin-loaded PEGylated nanostructured lipid carriers (BN-PEG-NLC) were developed to improve bioavailability of BN, to prolong retention time in vivo and to enhance its protective effect.

Methods: In this study, BN-PEG-NLC were prepared by the emulsion-evaporation and low temperature-solidification method using a mixture of glycerol monostearate and polyethylene glycol monostearate as solid lipids, and oleic acid as the liquid lipid. The physicochemical properties of NLC were characterized. The pharmacokinetic and pharmacodynamic behaviors of BN-PEG-NLC or BN-NLC were evaluated in acute MI rats.

Results and discussion: The particle size, zeta potential, and entrapment efficiency for BN-PEG-NLC were observed as 83.9?nm, ?32.1?mV, and 83.5%, respectively. The release profiles of BN from both BN-PEG-NLC and BN-NLC were fitted to the Ritger–Peppas modal, which presented burst release initially and prolonged release afterwards. Pharmacokinetics results indicated that BN-PEG-NLC exhibited a 7.2-fold increase in AUC in comparison to BN solution, while a 3-fold increase in comparison to BN-NLC. Biodistribution results revealed that BN-PEG-NLC exhibited higher heart drug concentration compared with BN-NLC as well as BN solution. In the present study, BN-PEG-NLC significantly ameliorated infarct size.

Conclusion: The results of the present study imply that PEG-NLC could be the biocompatible carriers for heart-targeted drug delivery to improve myocardial ischemia.     

Temperature-controlled power modulation compensates for heterogeneous nanoparticle distributions: a computational optimization analysis for magnetic hyperthermia

Purpose: To study, with computational models, the utility of power modulation to reduce tissue temperature heterogeneity for variable nanoparticle distributions in magnetic nanoparticle hyperthermia.

Methods: Tumour and surrounding tissue were modeled by elliptical two- and three-dimensional computational phantoms having six different nanoparticle distributions. Nanoparticles were modeled as point heat sources having amplitude-dependent loss power. The total number of nanoparticles was fixed, and their spatial distribution and heat output were varied. Heat transfer was computed by solving the Pennes’ bioheat equation using finite element methods (FEM) with temperature-dependent blood perfusion. Local temperature was regulated using a proportional-integral-derivative (PID) controller. Tissue temperature, thermal dose and tissue damage were calculated. The required minimum thermal dose delivered to the tumor was kept constant, and heating power was adjusted for comparison of both the heating methods.

Results: Modulated power heating produced lower and more homogeneous temperature distributions than did constant power heating for all studied nanoparticle distributions. For a concentrated nanoparticle distribution, located off-center within the tumor, the maximum temperatures inside the tumor were 16% lower for modulated power heating when compared to constant power heating. This resulted in less damage to surrounding normal tissue. Modulated power heating reached target thermal doses up to nine-fold more rapidly when compared to constant power heating.

Conclusions: Controlling the temperature at the tumor-healthy tissue boundary by modulating the heating power of magnetic nanoparticles demonstrably compensates for a variable nanoparticle distribution to deliver effective treatment.     

Poly(ortho ester) nanoparticles targeted for chronic intraocular diseases: ocular safety and localization after intravitreal injection

Treatment of posterior eye diseases is more challenging than the anterior segment ailments due to a series of anatomical barriers and physiological constraints confronted by drug delivery to the back of the eye. In recent years, concerted efforts in drug delivery have been made to prolong the residence time of drugs injected in the vitreous humor of the eye. Our previous studies demonstrated that poly(ortho ester) (POE) nanoparticles were biodegradable/biocompatible and were capable of long-term sustained release. The objective of the present study was to investigate the safety and localization of POE nanoparticles in New Zealand white rabbits and C57BL/6 mice after intravitreal administration for the treatment of chronic posterior ocular diseases. Two concentration levels of POE nanoparticles solution were chosen for intravitreal injection: 1.5?mg/ml and 10?mg/ml. Our results demonstrate that POE nanoparticles were distributed throughout the vitreous cavity by optical coherence tomography (OCT) examination 14 days post-intravitreal injection. Intraocular pressure was not changed from baseline. Inflammatory or adverse effects were undetectable by slit lamp biomicroscopy. Furthermore, we demonstrate that POE nanoparticles have negligible toxicity assessed at the cellular level evidenced by a lack of glia activation or apoptosis estimation after intravitreal injection. Collectively, POE nanoparticles are a novel and nontoxic as an ocular drug delivery system for the treatment of posterior ocular diseases.     

外加磁场对半乳糖化白蛋白磁性阿霉素纳米粒在大鼠体内分布影响的研究

目的观察半乳糖化白蛋白磁性阿霉素纳米粒(ADR-GHMN)在正常肝脏中的靶向性,并观察ADR-GHMN在全身各脏器的分布特征及外加磁场对其分布的影响.方法大鼠正中开腹,肝动脉插管并固定,肝动脉注射125I-ADR-GHMN(相当于阿霉素0.5 mg/kg),左外叶加磁场,磁场应用30 min,移去磁场后,动物立即处死;对照组:肝动脉注射ADR-GHMN,左外叶不加磁场,30min后,移去磁场后,动物立即处死,立即取靶区肝、非靶区肝、肾、心、肺、小肠、脾及周围血作γ计数.肝组织作病理切片.结果注入的纳米粒75～85%分布于肝脏,其它脏器极少.病理切片显示磁区小动脉见大量纳米粒存在,对照组及非磁区肝中纳米粒很少见.结论ADR-GHMN在正常肝组织中有明显的磁靶向性;在磁场作用下,ADR-GHMN主要分布于肝脏,其它脏器含量很少;试验组肾、心、肺、小肠、脾及外周血于对照组的放射活性比较明显降低,表明磁性物质的存在使这些脏器的相对药物暴露明显减少.     

Gold complex research in medical science. Difficulties with experimental design

Despite the use of gold complexes in modern medicine for over 100 years and the use of gold complexes in the management of rheumatoid disease for more than 60 years, the definitive mechanisms of action for efficacy and for toxicity have not been established. Gold is a group 1b metal in the periodic table with several oxidation states but it is only Au(I) which is active in the biological milieu. Gold sodium thiomalate is not only a polymeric structure, but also has the chiral ligand, thiomalic acid. Gold sodium thiomalate thus can exist in several different physical states which may have different biological activity. In addition the pharmacokinetic profile of gold complexes has been of little value in the understanding of either the mechanism of action, efficacy or toxicity for both the injectable and the oral gold complexes. Many authors have misinterpreted research data on the activities of gold complexes because they compared gold complexes of different structures, and gold complexes which exist at different pH. Experimental work in our laboratory has identified that gold sodium thiomalate is a mixture and can exist as either a yellow or a colourless solution. These have some similar but several different biological activities. Many factors contribute to the lack of understanding of the action of gold complexes. Some of these factors are related to the wide variation in physical structure and biological activities exhibited by these compounds.     

Some investigations into the nature and cause of massive fibrosis (MF) in the lungs of South African gold, coal, and asbestos mine workers

Samples from fibrotic lung lesions greater than 1 cm in diameter macroscopically (by definition, massive fibrosis; MF) were taken from the lungs of 9 randomly selected post-mortem cases of mine workers all showing a background of a pneumoconiosis. These samples were studied histologically, biochemically, and by X-ray diffraction and electron microscopy. As controls for the biochemical and X-ray diffraction investigations, nonfibrosed lung tissue was taken from the same specimens. The findings suggest that the higher quartz content may be the primary cause responsible for the MF formation in this series of cases, while other factors such as tuberculosis may play a part according to some relevant literature on MF. Although an area of MF appears macroscopically to be a solid lesion, on microscopy this is not the case and the lesion is composed of dense and sparse collagen bundles and cellular elements.     

Gold: an old drug still working in refractory pemphigus

BACKGROUND: The mainstay of treatment for pemphigus is systemic corticosteroids. Different adjuvants have been used to reduce side-effects of long-term corticotherapy. Gold is an anti-inflammatory drug used in autoimmune diseases, whose use has waned with the advent of new immunosuppressive agents. OBJECTIVE: To study the outcome of the use of intramuscular gold treatment of pemphigus vulgaris refractory to previous therapies. METHODS: Thirteen patients with pemphigus vulgaris who had failed to respond to several prior therapies were treated with aurothiomalate, as a steroid-sparing agent. Patients were monitored to assess disease activity and gold toxicity. RESULTS: Seven patients achieved complete remission. Four patients were able to taper prednisone doses, although pemphigus flared when prednisone was discontinued or reduced. Toxicity was observed in the other two patients. CONCLUSIONS: In 53.4% of the patients, the use of chrysotherapy resulted in the complete clearing of the disease, discontinuation of all systemic therapies and induced a long-term clinical remission. Prednisone doses were able to be reduced in the remaining 46.6%. Any side-effects were reversible with drug discontinuation. Gold therapy showed efficacy as a secondary line treatment in refractory pemphigus vulgaris.     

A retrospective mortality study of workers exposed to arsenic in a gold mine and refinery in France

A historical mortality study of a cohort of employees of a gold mining and refining company was carried out in Salsigne, France. A major goal of the study was to investigate the relationship between lung cancer mortality and exposure to arsenic, radon, silica, and other contaminants of the working environment. A twofold excess of lung cancer was found both among miners and smelters, mainly concentrated among workers who had experienced exposure to past levels of arsenic, radon, and silica. The consistency of the results in the mine and the refinery are suggestive of a carcinogenic risk from both soluble and insoluble arsenic, although the potential role of other factors cannot be dismissed. © 1994 Wiley-Liss, Inc.